New Oral Anticoagulants

Their Role in Stroke Prevention in

High-Risk Patients with Atrial Fibrillation

a b,
Sunita J. Ferns, MD, MRCPCH (UK) , Gerald V. Naccarelli, MD, FHRS *

KEYWORDS
 Anticoagulation  Novel oral anticoagulants  Atrial fibrillation  Factor IIa inhibitors
 Factor Xa inhibitors  Stroke

KEY POINTS
 Novel oral anticoagulants (NOACs) make up approximately 20% of new anticoagulant
prescriptions.
 NOACs have advantages of fixed-dose oral dosing, rapid onset and offset, and fewer in-
teractions with food and drugs compared with vitamin K antagonists (VKAs).
 NOACs are at least as effective as VKAs in patients with atrial fibrillation (AF) and venous
thromboembolism.
 NOACs have similar, if not lower, rates of serious hemorrhagic complications.
 Common errors in NOAC use include inappropriate patient selection, inappropriate dose
selection, and inappropriate monitoring.

INTRODUCTION

AF is the most common sustained arrhythmia and the leading cause of stroke in adults
worldwide.1,2 Traditionally, warfarin and other VKAs have been the mainstay treatment
option for patients with increased risk of stroke. Their use is, however, limited by a
narrow therapeutic index and interactions with multiple foods and other medications,
requiring frequent monitoring and dose adjustments.3 In the last 5 years, NOACs that
inhibit thrombin or activated factor X (fXa) have been approved as an alternative to
warfarin for stroke risk reduction in AF. Dabigatran etexilate, an oral reversible direct
thrombin inhibitor, was the first of these agents. It was followed by rivaroxaban,
apixaban, edoxaban, and, recently, betrixaban (phase 3 trials).4–7 The NOACs offer
several advantages over VKAs, such as rapid onset and offset of action, fewer drug
interactions, and an absence of an effect of dietary vitamin K intake on drug activity
(Fig. 1).8–12 This article reviews the pharmacologic and evidence-based data as well

a
Department of Pediatrics, University of North Carolina, College of Medicine, 101 Manning
Drive, Chapel Hill, NC 27599, USA; b Penn State Hershey heart and Vascular Institute, Penn
State College of Medicine, 500 University Drive, Hershey, PA 17033, USA
* Corresponding author.
E-mail address: gnaccarelli@hmc.psu.edu

Med Clin N Am 99 (2015) 759–780

http://dx.doi.org/10.1016/j.mcna.2015.02.006 medical.theclinics.com
0025-7125/15/$ – see front matter Crown Copyright Ó 2015 Published by Elsevier Inc. All rights reserved.
760 Ferns & Naccarelli

Fig. 1. Advantages and disadvantages of newer anticoagulants.

as the clinical characteristics of NOACs and their role in preventing stroke and thrombo-
embolic events in high-risk patients with nonvalvular AF (NVAF). Rivaroxaban and apix-
aban are also approved for the primary prevention of embolic events in patients who
undergo hip and knee replacement surgery. Dabigatran, rivaroxaban, and apixaban
are approved for deep vein thrombosis and pulmonary embolism (DVT/PE) treatment
and prevention. Edoxaban is awaiting US Food and Drug Administration (FDA) approval.

PHARMACOLOGY

NOACs are small molecules that specifically target individual clotting factors. As
thrombin is the final effector in blood coagulation, it is a logical target for newer agents.
Thrombin converts fibrinogen to fibrin and also amplifies its own generation by feed-
back activation of factors V, VIII, and XI. Thrombin is also a potent platelet agonist.
Therefore, thrombin inhibition not only attenuates fibrin formation but also reduces
thrombin generation and platelet activation. The NOACs target either thrombin or
fXa (Fig. 2). Dabigatran etexilate is a direct thrombin inhibitor, whereas rivaroxaban,
apixaban, edoxaban, and betrixaban work by direct fXa inhibition.2,13–19 Tables 1
and 2 detail the characteristics and drug interactions of the NOACs.20–36

Dabigatran Etexilate
Dabigatran etexilate, a substrate of the P-glycoprotein (P-gp) transporter, is a potent,
competitive, reversible inhibitor of thrombin that acts by binding clot-bound and free
thrombin with a high affinity and specificity. The prodrug, or etexilate form, is rapidly
converted to dabigatran by esterases and has an oral bioavailability of 6.5%. Drug
capsules are filled with tartaric acid, as drug absorption is enhanced with a low pH.
Levels usually peak 2 hours after oral administration. The half-life of dabigatran is
8 hours after single dose and 14 to 17 hours after multiple doses, enabling once or
twice daily administration. Dabigatran is primarily excreted by the kidneys, and there-
fore caution must be exercised in patients with renal dysfunction (creatinine clearance
 New Oral Anticoagulants 761

Fig. 2. Sites of action of newer anticoagulants.

[CrCl] <50 mL/min). Drug interactions are detailed in Table 2. Dyspepsia is the most
common reported side effect (see Table 1).2,8,37

Rivaroxaban
Rivaroxaban is an active compound that acts by binding reversibly to the active site of
fXa. It has an oral bioavailability of 80%, a rapid onset of action with a Cmax of 2 to
4 hours, and a half-life of 5 to 9 hours in young individuals that increases to 11 to
13 hours in the elderly. A third of the metabolized drug is excreted by direct renal
elimination and two-thirds is metabolized by the liver via cytochrome P450 (CYP)
3A4-dependent and independent pathways. Rivaroxaban is a substrate for P-gp.
Administration of drugs that are strong P-gp and CYP3A4 inhibitors, such as ketoco-
nazole or ritonavir, are contraindicated, as these increase plasma drug levels of rivar-
oxaban. Detailed drug interaction information are given in Table 2.9,17

Apixaban
Apixaban is a selective active site inhibitor of fXa. It does not require antithrombin III for
antithrombotic activity and inhibits free and clot-bound fXa and prothrombinase
activity. Although it has no direct effects on platelet aggregation, it indirectly inhibits
platelet aggregation induced by thrombin. By inhibiting fXa, apixaban decreases
thrombin generation and thrombus development. It is absorbed rapidly with a bio-
availability of 50%, and maximal plasma concentrations are achieved in 3 to 4 hours.
762 Ferns & Naccarelli

Table 1
Pharmacologic features of newer anticoagulants

Drug Dabigatran Rivaroxaban Apixaban Edoxabana Betrixabanb

Prodrug Yes No No No No
Factor inhibited Thrombin Xa Xa Xa Xa
Bioavailability (%) 6 80 60 50 35
Dosing 150 mg bid 20 mg daily 5 mg bid 60 mg daily 80 mg daily
110 mg bid 15 mg daily 2.5 mg bid 30 mg daily
15 mg daily
Absorption No effect 139% more No effect 6%–22% more
with food
Recommended No Yes No No No
intake with
food
GI side effects Dyspepsia None None None Nausea,
diarrhea
Absorption 12% to 30 % None None None —
with H2B/PPI
Peak plasma 2–3 2–4 1–4 1–2 3–4
levels (h)
Plasma trough 12–24 16–24 12–24 12–24 —
level (h)
Half-life (h) 14–17 5–9 12 9–11 19–24
Renal 80 35 25 35 7
clearance (%)
Liver metabolism No Yes Yes Mild No
(CYP3A4)
P-glycoprotein Yes Yes Yes Yes Yes
inhibition

Abbreviations: GI, gastrointestinal; H2B, histamine-2 blockers; PPI, proton pump inhibitors.
a
Awaiting FDA approval.
b
In phase 3 trials.

The half-life is 8 to 14 hours. It exhibits linear pharmacokinetics and is 87% plasma pro-
tein bound. Elimination is via multiple pathways, including hepatic metabolism via
CYP3A4 and renal and intestinal excretion. It is also a substrate for P-gp transporter.10
Edoxaban
Edoxaban is another highly selective, competitive inhibitor of fXa. Because it is rapidly
absorbed with a peak plasma concentration in 1.5 hours and a half-life of 10 to 14 hours,
it may be given once daily. The bioavailability is 62%, and its activity is not influenced by
food intake. The plasma concentrations of edoxaban closely correlate with suppres-
sion of thrombin generation and inhibition of a range of platelet activation parameters.
One-third of the drug is eliminated via the kidney, and the remainder is excreted in the
feces. Strong P-gp inhibitors, such as dronedarone, quinidine, and verapamil, require a
50% dose reduction in edoxaban. The effects of edoxaban may also be increased in
patients with a body weight of 60 kg or less and moderate renal impairment.11,12
Betrixaban
Betrixaban is an oral once-daily fXa inhibitor. Unlike other prior agents, it has a long
half-life of 15 to 20 hours and extrarenal clearance. Therefore, it can be used in
 Table 2
Drug interactions of newer oral anticoagulants

Drug Mechanism of Interference Dabigatran Rivaroxaban Apixaban Edoxabana Betrixabanb

Antacids Absorption 12% to 30% No effect No data No effect —
Antiarrhythmics
Amiodarone P-gp 112% to 60% Minor effect No data No effect 1260%
Dronedarone P-gp & CYP3A4 170% to 100% No data No data 185% —
Digoxin P-gp No effect No effect No data No effect No effect
Verapamil P-gp & CYP3A4 120% to 180% Minor effect No data 153% 1450%
Diltiazem P-gp & CYP3A4 No effect Minor effect 140% No data —
Antifungals
Ketoconazole CYP3A4 1140% to 150% 1160% 1100% No data 1230%
Antiretrovirals
HIV protease inhibitors P-gp & CYP3A4 No data 1153% Strong increase No data —
Antiepileptics
CMZ, phenytoin, phenobarbitone P-gp & CYP3A4 66% 50% 54% 30% —
Miscellaneous

New Oral Anticoagulants

Rifampicin, St. John’s wort P-gp & CYP3A4 66% 50% 54% 30% —
Cyclosporin, tacrolimus P-gp No data 150% No data No data —

Abbreviations: CMZ, carbamazepine; CYP, cytochrome P450; HIV, human immunodeficiency virus.
a
Awaiting FDA approval.
b
In phase 3 trials.

763
764 Ferns & Naccarelli

patients with severe renal impairment. In addition, betrixaban has properties that may
allow it to demonstrate efficacy without the increase in the rate of major bleeding seen
with other fXa inhibitors in acute medically ill patients. It has a low peak-to-trough drug
concentration ratio that minimizes anticoagulant variability. Lack of CYP3A4 meta-
bolism reduces the risk of drug-drug interactions. Its effects can potentially be
reversed with alfa (PRT4445), an investigational recombinant fXa inhibitor antidote.38

DRUG MONITORING WITH NOVEL ORAL ANTICOAGULANTS

The current NOACs do not require routine blood monitoring, and neither dosing nor
dosage intervals should be altered in response to changes in laboratory coagulation pa-
rameters. However, testing may be performed in case of major bleeding, thrombotic
events, or urgent surgery. Testing may also be required in cases of suspected overdos-
ing, severe renal or hepatic insufficiency, or suspected drug interactions. Table 3 lists
the standard coagulation tests and their applicability in patients administered
NOACs.39–42 Unfortunately, some of these tests are not readily available in all centers.
When interpreting a test, it is essential to know when the drug was administered in
relation to the blood draw, as a sample taken at peak levels demonstrates a much
higher effect than one drawn at trough concentrations. With dabigatran specifically,
there is a close correlation between plasma concentration and the degree of antico-
agulant effect. If the blood level is 30 ng or less, one can proceed with the urgent
surgery on NOACs; however, if the level is very high (eg, overdose), the risk of hem-
orrhage is high and dialysis should be considered before surgery. The activated par-
tial thromboplastin time (aPTT) may also be useful to indirectly assess dabigatran
activity; however, dabigatran has little or no effect on the prothrombin time (PT)

Table 3
Applicability of coagulation assays in patients administered NOACs

Drug Coagulation
Laboratory Phase
Test Availability Studied Dabigatran Rivaroxaban Apixaban Edoxaban
PT Yes Extrinsic/ No Prolonged No Prolonged
common
pathway
aPTT Yes Intrinsic/ Yes (trough No No Prolonged
common >2 ULN
pathway bleed)
INR Yes Extrinsic/ No No No No
common
pathway
dTT Limited DTI activity Yes (trough No No No
>200
ng/mL-bleed)
ECT Limited DTI activity Yes (trough No No No
>3 ULN
bleed)
Anti-Xa Limited Specific NA Yes Yes Yes
activity factor
Factor IIa NA — Yes No No —

Abbreviations: aPTT, activated partial thromboplastin time; DTI, direct thrombin inhibitor; dTT,
diluted thrombin time; ECT, ecarin coagulation time; INR, International normalized ratio; PT, pro-
thrombin time; UNL, upper limit of normal.
 New Oral Anticoagulants 765

and international normalized ratio (INR).39,40 The diluted thrombin time assay may be
useful to indirectly assess dabigatran concentrations as it displays a direct linear
relationship. The ecarin clotting time assay provides a direct measure of the activity
of direct thrombin inhibitors, but both these tests are not readily available.40–42
For rivaroxaban the PT may provide a qualitative assessment, with a concentration-
dependent prolongation of the PT noted. There are currently no such data available
for edoxaban and apixaban. Anti-fXa assays are available at limited centers to assess
plasma concentrations of the fXa inhibitors; however, there are no clear data showing
association between drug levels and the risk of bleeding. The aPTT and INR do not pro-
vide meaningful information in the evaluation of fXa inhibitor and should not be used.20,43

TRIALS ON NEWER ANTICOAGULANTS

Multiple trials have been carried out to compare the use of NOACs with warfarin:
RE-LY (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With
Dabigatran Etexilate), dabigatran; ROCKET AF (Rivaroxaban versus Warfarin in Non-
valvular Atrial Fibrillation), rivaroxaban; ARISTOTLE (Apixaban for the Prevention of
Stroke in Subjects With Atrial Fibrillation), apixaban; ENGAGE TIMI-AF 48 (Global
Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard
Practice of Dosing With Warfarin in Patients With Atrial Fibrillation), edoxaban; and
APEX (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study),
betrixaban (phase 3 stage). Comparisons are detailed in Table 4. These trials did not
include patients with mitral stenosis or any type of prosthetic heart valves or those
likely to need a valve replacement in the near future.

Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) With Dabigatran

Etexilate
 This study compared dabigatran to warfarin in 18,113 patients with AF at risk for
stroke (PROBE (Prospective, randomized, outcome blinded trial) design).
 The mean CHADS2 (Diagnosed heart failure, past or current [1 point], Hyperten-
sion treated or untreated [1 point], Age  75 years [1 point], Diabetes Mellitus
[1 point], Secondary prevention in patients with prior ischemic stroke, TIA or
thromboembolism [2 points]) score was 2.1, and median follow-up duration
was 2 years.
 Patients were randomly assigned to 1 of 2 blinded doses of dabigatran, 110 or
150 mg twice daily, or open-label, dose-adjusted warfarin to study primary
outcome of stroke or systemic embolization.
 This condition occurred at rates of 1.71% per year in the group assigned to
warfarin; 1.54% per year in those randomized to dabigatran, 110 mg twice daily
(P<.001 for noninferiority to warfarin); and 1.11% per year with dabigatran,
150 mg twice daily (P<.001 for superiority to warfarin).
 Significantly lower rates of intracerebral hemorrhage were noted with both doses
of dabigatran when compared with warfarin.
 The higher dose of dabigatran yielded a higher rate of gastrointestinal bleeding
but a similar rate of major bleeding as compared with warfarin.
 All-cause mortality was lower with dabigatran (4.13% per year for warfarin;
3.75% per year for dabigatran, 110 mg twice daily; and 3.64% per year for dabi-
gatran, 150 mg twice daily) but did not reach statistical significance (P 5 .13 and
P 5 .051 for the 110 and 150 mg twice daily doses, respectively).2
 Following RE-LY, dabigatran, 150 mg twice daily, was approved to reduce the
risk of stroke and systemic embolism in patients with NVAF worldwide.
 766
Table 4
Comparison of trials studying newer anticoagulants for stroke prevention in AF

Ferns & Naccarelli

Trial RE-LY ROCKET-AF ARISTOTLE AVERROES ENGAGE-AF EXPLORE Xa
Drug Dabigatran Rivaroxaban Apixaban Apixaban Edoxaban Betrixaban
Dose 110 mg bid 20 mg daily 5 mg bid 5 mg bid 30 mg daily 40, 60, 80
150 mg bid 15 mg dailya 2.5 mg bida 2.5 mg bida 60 mg daily mg daily
Control Warfarin Warfarin Warfarin Aspirin Warfarin Enoxaparin
Year 2009 2011 2011 2010 2013 2012
N 18,113 14,264 18,201 5599 21,105 561
Study design PROBE Double blind, Double blind, Double blind Double blind, Randomized
double dummy, double dummy, double dummy, blinded open
noninferiority noninferiority noninferiority label
Study population Nonvalvular AF Nonvalvular AF with Nonvalvular AF with Nonvalvular AF with Nonvalvular AF with Nonvalvular AF and
with >stroke risk previous stroke/ 1 stroke risk 1 stroke risk 2 stroke risk AFl with at least 1
TIA/systemic factor factor, VKA factors risk factor for
embolism or 2 unsuitable, stroke
stroke risk factor refused, or failed
AF type 2:1 4.5:1 5.67:1 2.33:1 3:1 1.18:1
Persistent/
permanent:
paroxysmal
Age (median) (y) 71 (mean) 73 70 70 72 74
Women (%) 37 40 36 41 39 33.5
CHADS2 (mean) 2.1 3.5 2.1 2 2.8 2.2
VKA naive (%) 50 38 43 60 39 13
Prior CVA/TIA (%) 20 54.8 19.4 14 28 —
TTR (mean) (%) 64 55 62 NA — 63.4
Median FU (y) 2 1.9 1.8 1.1 2.8 0.4
Primary efficacy Stroke or STE Stroke or STE Stroke or STE Stroke or STE Stroke or STE Time to major or
end point clinically relevant
nonmajor bleeding
 Primary outcome HR 0.66 0.88 0.79 0.45 0.79 0.14, 0.7, 0.75b
Hem CVA rate 0.24 0.59 0.51 0.21 0.26 —
Ischemic CVA HR 0.75 0.99 0.92 0.37 1 —
Secondary efficacy Ischemic, Ischemic or Ischemic, Ischemic, Stroke, systemic —
end point hemorrhagic, or hemorrhagic hemorrhagic or hemorrhagic, embolism,
unspecified stroke, stroke, stroke stroke of unknown unspecified stroke, cardiovascular and
MI, PE, outcome, non-CNS cause, all-cause disabling/fatal all-cause death
hospitalization, embolism, MI, all- death, MI, PE, or stroke, MI, all-
and all-cause and cause death, deep vein cause and vascular
vascular death vascular and thrombosis death
nonvascular death
Primary safety Major bleeding Major and clinically Major bleeding Major bleeding Major bleeding Time to major or
end point (including life- relevant nonmajor (including (including clinically relevant
threatening, non– bleeding intracranial, other intracranial, nonmajor bleeding
life-threatening, organ, and GI extracranial, or
and GI bleeding) bleeding) unclassified and
fatal bleeding)
Secondary Minor bleeding, Minor bleeding Major or clinically Clinically relevant Major and clinically Any bleeding
safety end point major or minor (eg, epistaxis, relevant nonmajor nonmajor and relevant nonmajor
bleeding, hematuria) bleeding minor bleeding bleeding,
intracranial and incidence of liver
extracranial enzyme/bilirubin
bleeding, net abnormalities
clinical benefit

New Oral Anticoagulants

Major bleeding 3.1 3.6 2.13 3.1 2.75 —
rate (%)
All causes 3.64 1.9 1.87 3.5 3.99 —
death (%/y)

Abbreviations: AFl, atrial flutter; CNS, central nervous system; CVA, cerebrovascular accident; FU, follow-up; GI, gastrointestinal; HR, hazard ratio; MI, myocardial
infarction; PE, pulmonary embolism; STE, systemic embolization; TIA, transient ischemic attack; TTR, time in treatment range.
a
Select patients.
b
Doses of betrixaban.

767
768 Ferns & Naccarelli

 Recently, this drug was approved by the FDA for treatment of DVT and PE.
 Although patients with severe renal impairment (CrCl <30 mL/min) were excluded
from RE-LY, the FDA approved a dose of 75 mg twice daily for patients with CrCl
15 to 30 mL/min, based on pharmacokinetic modeling.

Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation

 This study was a double-blind, double-dummy study carried out over a median
follow-up of 1.9 years comparing rivaroxaban with warfarin in 14,264 patients
with NVAF who were at increased risk for stroke.17
 The study included patients with high stroke risk with a mean CHADS2 score of
3.5, with 55% of patients having a prior stroke or transient ischemic attack (TIA).
 Study arm patients received fixed-dose rivaroxaban, 20 mg once daily (15 mg
daily for those with CrCl 30–49 mL/min).
 Rivaroxaban was superior to warfarin (hazard ratio [HR], 0.88; P 5 .015) in
preventing stroke or systemic embolism.
 Rivaroxaban reduced the frequency of hemorrhagic strokes compared with
warfarin by 41% (HR, 0.59).

Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation

 A total of 18,201 patients with NVAF and at least 1 additional risk factor for stroke
(mean CHADS2, 2.1) were evaluated in a double-blind study comparing apixaban
(5 mg twice daily [2.5 mg twice daily in high-risk patients]) with warfarin.
 The lower dose was used for those with 2 or more of the following factors asso-
ciated with increased drug exposure: age greater than 80 years, body weight less
than 60 kg, or serum creatinine level greater than 1.5 mg/dL. About 19% of these
patients had a previous TIA, stroke, or systemic embolism.
 Apixaban was superior to warfarin in preventing stroke or systemic embolism (HR
with apixaban, 0.79; 95% confidence interval [CI], 0.66–0.95; P<.001 for nonin-
feriority; P 5 .01 for superiority).
 Apixaban also caused less bleeding and resulted in lower mortality (HR, 0.89;
95% CI, 0.80–0.99; P 5 .047) and reduced hemorrhagic stroke by 49%
compared with warfarin (P 5 <.001).16

A Phase III Study of Apixaban in Patients With Atrial Fibrillation

 This trial compared apixaban and aspirin in 5599 patients with AF at increased
risk for stroke unsuitable for VKA therapy.
 Apixaban reduced the risk of stroke or systemic embolism without significantly
increasing the risk of major bleeding or intracranial hemorrhage.
 The trial was terminated early when apixaban was shown to be superior in
reducing the risk of stroke or systemic embolism without increases in the risk
of major bleeding or hemorrhagic stroke.44
Based on the results of the ARISTOTLE and AVERROES trials, apixaban has been
approved for stroke prevention in patients with AF.

Global Study to Assess the Safety and Effectiveness of Edoxaban (DU-176b) vs

Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation
 This trial is the most recent and largest ever clinical trial on NOACs.
 This trial is of double-blind design, studying 21,105 patients who were random-
ized to receive edoxaban, 30 and 60 mg once daily, in comparison with warfarin
for prevention of stroke in patients with AF.
 New Oral Anticoagulants 769

 Both doses were halved if the patient had poor renal function (CrCl, 30–50 mL/
min), weight 60 kg or less, or concomitant use of potent P-gp inhibitors
(verapamil, quinidine, or dronedarone).
 Edoxaban 30 or 60 mg daily was noninferior to warfarin for the primary efficacy
end point of stroke or systemic thromboembolism. However, in the intention-to-
treat analysis, there was a trend favoring high-dose edoxaban versus warfarin
(P 5 .08) and an unfavorable trend with low-dose edoxaban versus warfarin
(P 5 .10).
 The rates of major bleeding including intracranial hemorrhage were significantly
lower with both doses of edoxaban than with warfarin.
 Gastrointestinal bleeds were higher with high-dose edoxaban but lower with the
low dose.45
 Based on these results, the drug is under consideration by the FDA for approval
for the reduction in risk of stroke and systemic embolic events in patients with
NVAF, as well as for the treatment of DVT or PE.
Study of the Safety, Tolerability and Pilot Efficacy of Oral Factor Xa Inhibitor
Betrixaban Compared to Warfarin
 This trial is a phase 2, randomized, parallel-group, dose-finding multinational
study of the safety, tolerability, and pilot efficacy of 3 blinded doses of betrixaban
compared with open-label dose-adjusted warfarin in patients with NVAF with at
least 1 risk factor for stroke.
 The primary end point was the time to major or clinically relevant nonmajor
bleeding, and the secondary end point was time to any bleeding, death, stroke,
myocardial infarction, or systemic embolism.
 The secondary objective was to study the pharmacokinetics of betrixaban.
 Betrixaban was well tolerated and had similar or lower rates of bleeding
compared with well-controlled warfarin in patients with AF at risk for stroke.46

CLINICAL CONSIDERATIONS
Switching Between Anticoagulation Regimens
1. Switching to an NOAC: The aim is to minimize the risk of bleeding while maintaining
the therapeutic effect during the transition between various drugs. While switching
from warfarin to one of the newer anticoagulants, warfarin therapy may be stopped
and NOAC therapy started when the INR is less than 2 in the case of dabigatran and
apixaban and less than 3 in the case of rivaroxaban. For INR higher than these rec-
ommended values, the half-life of warfarin and the current INR should be taken into
account to estimate when the INR value will likely drop to less than the threshold for
the specific NOAC and a laboratory draw should be scheduled around that time. To
switch from one NOAC to another, just substituting a new drug at the next dose
should be considered. In switching from intravenous unfractionated heparin
(UFH), the use of NOAC may be started 2 hours after heparin is discontinued,
and in switching from low-molecular-weight heparin (LMWH), NOAC use may be
initiated at the next due dose of LMWH. NOAC therapy can be started immediately
after use of aspirin and clopidogrel is discontinued without waiting for the next due
dose.
2. Switching from an NOAC: While switching to a VKA, it may take several days before
an INR in the therapeutic range is obtained. Therefore, the NOAC should be admin-
istered concomitantly with the VKA until the INR is in a desired range. Owing to drug
interactions between the 2 agents, it is advisable to test the INR just before the next
intake of the NOAC during simultaneous administration and retest 24 hours after
770 Ferns & Naccarelli

the last dose of the NOAC. The INR should also be closely monitored for the first
couple of months until stable values are reached. Use of heparin (UFH or LMWH)
may be started when the next dose of NOAC is due.47

Dosing Errors
1. Missed doses: For NOACs with twice-daily and daily dosing regimens, a missed
dose may be taken up till 6 and 12 hours, respectively, after the next scheduled
dose, and subsequent dosing should be resumed as normal. If this is not possible,
the dose should be skipped and the next dose should be taken at the scheduled
time.
2. Double doses: For NOACs with a twice-daily regimen, the next planned dose should
be skipped and twice-daily intake restarted in 24 hours. In daily dosing regimens, the
normal regimen should be continued without skipping the next daily dose.
3. Uncertainty about dose: For twice-daily regimens, the planned dosing regimen
could be continued without retaking the dose about which the patient was uncer-
tain. For daily dosing regimens, another pill could be taken and then the planned
dose regimen should be continued the next day.
4. Overdosing: Overdosing may occur intentionally or unintentionally or in the pres-
ence of concurrent events such as renal insufficiency. Depending on the clinical
status and the amount of suspected overdose, the patient should be hospitalized.
In case of overdose without bleeding, a wait-and-watch approach is reasonable
given the short plasma half-life of NOACs. If the ingestion is recent, activated char-
coal may be used to reduce absorption. Further management of bleeding is dis-
cussed- in the section on reversing anticoagulation effect.47

Reversal of Anticoagulation Effect

Reversal may be needed in the following situations:
1. Emergent surgical intervention: Attempts should be made to defer surgery for at
least 12 hours, and ideally 24 hours, after the last dose. Evaluation of common
coagulation tests as mentioned in Table 3 may be undertaken if there is concern
regarding waning in anticoagulation effect. The risk of bleeding is definitely
increased and should be weighed against the urgency of intervention.
2. Management of bleeding complication: Specific antidotes and rapid (routine) quan-
titative measurements of anticoagulant effect are currently not available. Unlike in
the case of VKAs, the plasma levels of NOACs may block newly administered coag-
ulation factors. As the bleeding profile of NOACs, in particular that of intracranial
and other life-threatening bleeding, is more favorable than that of warfarin, urgent
restoration of coagulation may not be required in non–life-threatening bleeds.
Restoration of coagulation does not necessarily equal good clinical outcome. In
the case of dabigatran, activated charcoal may also be used for adsorbing drug
from the stomach if ingestion has been recent, and hemodialysis may be used to
remove dabigatran from the blood. Fig. 3 outlines the management options in
case of bleeding.40,48–53

Antidotes
1. A specific antidote for dabigatran has been developed and tested in animals but
not yet in humans. The antidote has structural similarities with thrombin but an
affinity for dabigatran that is about 350 times stronger than the affinity for thrombin.
This antidote does not bind to known thrombin substrates and has no activity in
coagulation tests or in platelet aggregation.54
 New Oral Anticoagulants 771

Fig. 3. Management of bleeding in patients administered NOACs. FFP, fresh frozen plasma;
PRBC, packed red blood cells.

2. Betrixaban reversibility is being studied with andexanet alfa (PRT4445), an

investigational recombinant fXa inhibitor antidote.38

Planned Surgery
1. Discontinuation of NOACs is not required for minor surgical procedures or those
with a low bleeding risk. Procedures that carry a moderate to high risk of bleeding
require a temporary interruption in the use of NOAC.47,55,56
2. Bridging was proposed in patients with AF with higher thromboembolic risk treated
with VKAs but is not required in case of NOACs, as the predictable waning of the
anticoagulation effect allows properly timed short-term cessation and reinitiation
of NOAC therapy before and after surgery.
3. Although the aPTT and PT may provide a semiquantitative assessment of dabiga-
tran and fXa inhibitors, respectively, it is not routinely recommended to aim at
normalization of these clotting functions before surgery. Further information
regarding specific categories is present in Fig. 4.

Atrial Fibrillation Ablation

1. AF ablations are considered high risk for bleeding because of the potential
for multiple transeptal punctures and extensive case time. However, routine
discontinuation of anticoagulation for 48 hours postprocedure is not advis-
able because of the high risk of thromboembolic complications immediately
postprocedure.
2. There is controversy regarding the appropriate time to stop and start anticoagula-
tion for AF ablations; Lakkireddy and colleagues57 showed that NOACs given
24 hours before procedure and resumed within 3 hours following hemostasis
were associated with a low complication rate, whereas Winkle and colleagues58
advocated discontinuing NOACs for 36 hours before procedure and resuming at
22 hours postprocedure, with an interim bridge of 2 doses of enoxaparin (immedi-
ately and at 12 hours after ablation).
3. The VENTURE-AF study is following up 200 patients to prospectively evaluate the
safety of rivaroxaban and VKAs around an AF ablation.59
772 Ferns & Naccarelli

Fig. 4. Management of NOACs in surgical interventions. ICD, implantable cardioverter defi-

brillator; RF, radio frequency.

Cardioversion
1. In patients with AF of greater than 48 hours or unknown duration, oral anticoagula-
tion should be therapeutic for at least 4 weeks before cardioversion, otherwise a
transesophageal echocardiography (TEE) should be performed to rule out left-
sided thrombi.60
2. After cardioversion, oral anticoagulation should be continued without interruption
for another 4 weeks.
3. As there is no readily available coagulation assay for any of the NOACs, it is essen-
tial to establish and document compliance before cardioversion. A TEE should be
performed if there are doubts about compliance.
4. In a subanalysis of the RE-LY trial, the frequencies of stroke and major bleeding
within 30 days of cardioversion on both doses of dabigatran were low and compa-
rable to those on warfarin, with or without TEE guidance.61
5. The X-veRT (Explore the Efficacy and Safety of Once-daily Oral Rivaroxaban for the
Prevention of Cardiovascular Events in Subjects With Nonvalvular Atrial Fibrillation
Scheduled for Cardioversion) trial showed that oral rivaroxaban not only was a safe
and effective alternative to VKAs but also allowed earlier cardioversion compared
with patients administered oral VKAs.62

POTENTIAL SOURCES OF ERROR IN NOVEL ORAL ANTICOAGULANT USE

The sources of error in Fig. 5 may be seemingly obvious but have been the most com-
mon source of error and associated complications in NOACs use.
 New Oral Anticoagulants 773

Fig. 5. Sources of error in NOAC use.

SPECIAL CONSIDERATIONS
Renal Failure
Chronic kidney disease (CKD) is associated with a relative increase in bleeding risk in
patients administered NOACs. NOACs are, however, still a reasonable choice for
anticoagulant therapy in patients with AF with mild or moderate CKD. Dabigatran,
which is primarily cleared renally, may not be the NOAC of first choice in patients
with known CKD, especially stage III or higher. A lower dose of dabigatran, at
75 mg twice daily, has been approved by the FDA for CrCl less than 30 mL/min.
Dose reductions have been studied prospectively with apixaban (2.5 mg twice daily)
and rivaroxaban (15 mg daily), and these may be more appropriate choices than
dabigatran.44,63 Renal function should be monitored at least every 6 months in
patients with known renal dysfunction and yearly in patients with normal function
at start of drug treatment. In the absence of clinical data or experience, NOAC ther-
apy should be avoided in patients with AF who are on hemodialysis. VKAs may be a
more suitable alternative, even though the benefit of VKAs in hemodialysis has not
been proved.

Malignancy
Malignancy and AF occur in the elderly, and the use of NOACs in patients with ma-
lignancies is appropriate. Malignancies can predispose to stroke, and malignancies
and their therapies are associated with a higher bleeding risk.64 In all NOAC trials
including Venous thromboembolism (VTE) trials, active malignancy was an exclusion
criterion. When anticoagulant therapy needs to be initiated in a patient with malig-
nancy, therapy with VKAs or heparins should be considered over NOACs, because
of the clinical experience with these substances, the possibility of close monitoring,
and reversal options. If the patient is on established anticoagulant therapy including
NOACs when the malignancy is detected, the current anticoagulant should be
continued whenever possible. Careful clinical monitoring for signs of bleeding and
regular blood counts including platelets and liver and renal function must be
performed.47
 774
Ferns & Naccarelli
Table 5
Comparison of recent trials studying newer anticoagulants for secondary prevention of DVT/PE

Trial RE-COVER EINSTEIN-DVT EINSTEIN-PE AMPLIFY HOKUSAI VTE APEX

Drug Dabigatran Rivaroxaban Rivaroxaban Apixaban Edoxaban Betrixaban
Dose 150 mg bid 15 mg bid (3 wk) 15 mg bid (3 wk) 10 mg bid (1 wk) 60 mg Daily 80 mg Daily
20 mg Daily 20 mg Daily 5 mg bid (6 mo)
Control Warfarin Enoxaparin 1 Enoxaparin 1 Enoxaparin 1 Enoxaparin or Enoxaparin
warfarin warfarin warfarin UFH 1 warfarin
Year 2008 2010 2011 2012 2013 2015 (estimate)
N 2564 3449 4832 5395 8250 6850 (estimate)
Study design Double blind, Randomized Randomized Randomized, Randomized, Double blind,
double dummy open label open label double-blind double-blind double dummy
study study
Age (mean) (y) 55 56 57.8 57 55.7 —
Women (%) 42 43 46 41 42.7 —
Prior VTE (%) 25.5 19 19 — 19 —
TTR (%) 59.9 57.7 62.7 61 63.5 —
Index event DVT 69 98.7 0 65 60 —
PE (%) 21 0 74.9 25.2 30
DVT&PE (%) 9.5 0.7 25.1 9.4 10
 Duration of 7 3, 6, 12 3, 6, 12 7 12 —
follow-up (mo)
Primary efficacy VTE or Recurrent VTE Recurrent VTE Recurrent Recurrent VTE VTE (DVT and/or PE) and
end point related death VTE or death VTE Death thro D35
Recurrent VTE HR 1.09 0.68 1.12 0.85 0.89 —
Major bleed HR 0.73 0.18 0.9 0.31 0.84 —
Clinically relevant 0.62 0.93 0.49 0.44 0.81 —
nonmajor
bleed HR
Death HR 1 0.67 1.13 0.79 1.05 —
Primary safety Major bleeding, Major bleeding, Major bleeding, Major bleeding, Major bleeding, Major bleeding,
end point clinically relevant clinically relevant clinically relevant clinically relevant clinically relevant clinically relevant
nonmajor bleed nonmajor bleed nonmajor bleed nonmajor bleed nonmajor bleed nonmajor bleed

Abbreviation: TTR, Time in therapeutic range.

AMPLIFY, Oral Apixaban for the Treatment of Acute Venous Thromboembolism; APEX, Acute Medically Ill VTE Prevention With Extended Duration Betrixaban
Study; EINSTEIN-DVT, Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis; EINSTEIN-PE, Oral Direct Factor Xa
Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism - The EINSTEIN PE Study; HOKUSAI VTE, Comparative Investigation of Low
Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/
or Lung Blood Clots; RE-COVER, Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous
Thromboembolism.

New Oral Anticoagulants

775
776 Ferns & Naccarelli

NOVEL ORAL ANTICOAGULANTS IN DEEP VEIN THROMBOSIS/PULMONARY

EMBOLISM

Although this article does not discuss the role of NOACs in PE and DVT in detail, high-
lights of the major trials studying the use of NOACs for DVT and PE are summarized in
Table 5.38,65–69

SUMMARY

Based on efficacy, safety, and ease of use, NOACs will likely replace VKAs for many if
not most patients with AF. Novel anticoagulants have a lower rate of intracranial hem-
orrhage compared with VKAs. The incidence of other life-threatening bleeds is similar
if not lower. Dose adjustments need to be made based on renal function and
advanced age. There is at present a need for an antidote for these new drugs.

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